Angiotensin II (Ang II) induces deleterious changes in cellular iron metabolism and increases the generation of reactive oxygen species. This leads to an impairment of neuronal and vascular function. However, the mechanism underpinning Ang II-induced changes in iron metabolism is not known. We hypothesized that Ang II-induced ferritin degradation and an increase in the labile iron pool are mediated by the c-Jun N-terminal kinase (JNK)/p66Shc/ITCH signaling pathway. We show that Ang II treatment induced ferritin degradation in an endothelial cell lines derived from the bovine stem pulmonary artery (CPAE), human umbilical vein endothelial cells (HUVEC), and HT22 neuronal cells. Ferritin degradation was accompanied by an increase in the labile iron pool, as determined by changes in calcein fluorescence. The JNK inhibitor SP600125 abolished Ang II-induced ferritin degradation. Furthermore, the effect of Ang II on ferritin levels was completely abolished in cells transfected with vectors encoding catalytically inactive variants of JNK1 or JNK2. CPAE cells expressing inactive ITCHor p66Shc (substrates of JNK kinases) were completely resistant to Ang II-induced ferritin degradation. These observations suggest that Ang II-induced ferritin degradation and, hence, elevation of the levels of highly reactive iron, are mediated by the JNK/p66Shc/ITCH signaling pathway.
Keywords: angiotensin II; free radical; iron.